HPV VLPs-based RNA-delivery system for synergistic BCL-2 silencing and mitochondrial apoptosis in NSCLC cells

IF 7.9 2区材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY

Materials & Design Pub Date : 2025-09-27 DOI:10.1016/j.matdes.2025.114820

Meng-Fan Feng , Jinyu Zhu , Li-Miao Qin , Xianghui Yu , Haihong Zhang , Xiao-Xia Han , Yuqing Wu

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Abstract

Non-small cell lung cancer (NSCLC) resists apoptosis and lacks targeted therapies. We developed a tetra-functional assembly, siRNA_D-pep@VLP-SP5-2, integrating BCL-2 siRNA and a cationic mitochondrial destabilization D-peptide within the SP5-2-modified HPV virus-like particle (VLP). This multifunctional assembly integrate: (1) SP5-2-driven tumor targeting precision, (2) VLP-improved cellular uptake, (3) siRNA-induced BCL-2 silencing (70 % knockdown), and (4) D-peptide-triggered Cyt c release and mitochondrial apoptosis. In cells, siRNA_D-pep@VLP-SP5-2 induced 91 % apoptosis of A549 cells, while in A549 tumor-bearing mice, it reduced 78.2 % tumor growth without systemic toxicity. This multifunctional assembly pioneer’s co-delivery of gene and therapeutical peptide synergistically, overcoming key barriers in NSCLC precision therapy. In particular, the thoroughly revealed apoptotic kinetics for the RNAi therapeutics and peptide-mediated cytotoxicity, together with the modular design using VLP opens new avenues for multimodal cancer therapeutics, expecting to transition from “limit-target inhibition” toward “dynamic network-level regulation”, thereby establishing a paradigm-shifting framework for solid tumor treatment.

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基于HPV vlps的rna递送系统协同BCL-2沉默和非小细胞肺癌细胞线粒体凋亡

非小细胞肺癌（NSCLC）抵抗细胞凋亡，缺乏靶向治疗。我们开发了一个四功能组件siRNA_D-pep@VLP-SP5-2，将BCL-2 siRNA和阳离子线粒体不稳定d肽整合到sp5 -2修饰的HPV病毒样颗粒（VLP）中。该多功能组件集成：(1)sp5 -2驱动的肿瘤靶向精度，(2)vlp改善的细胞摄取，(3)sirna诱导的BCL-2沉默（70%敲低），以及(4)d肽触发的Cyt - c释放和线粒体凋亡。在细胞中，siRNA_D-pep@VLP-SP5-2诱导了91%的A549细胞凋亡，而在A549荷瘤小鼠中，它减少了78.2%的肿瘤生长，无全身毒性。这种多功能组装先驱的基因和治疗肽协同递送，克服了非小细胞肺癌精确治疗的关键障碍。特别是，彻底揭示了RNAi疗法和肽介导的细胞毒性的凋亡动力学，以及使用VLP的模块化设计，为多模式癌症治疗开辟了新的途径，有望从“限靶抑制”过渡到“动态网络水平调节”，从而建立一个范式转换框架，用于实体肿瘤治疗。

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来源期刊

Materials & Design Engineering-Mechanical Engineering

CiteScore

14.30

自引率

7.10%

发文量

1028

审稿时长

85 days

期刊介绍： Materials and Design is a multi-disciplinary journal that publishes original research reports, review articles, and express communications. The journal focuses on studying the structure and properties of inorganic and organic materials, advancements in synthesis, processing, characterization, and testing, the design of materials and engineering systems, and their applications in technology. It aims to bring together various aspects of materials science, engineering, physics, and chemistry. The journal explores themes ranging from materials to design and aims to reveal the connections between natural and artificial materials, as well as experiment and modeling. Manuscripts submitted to Materials and Design should contain elements of discovery and surprise, as they often contribute new insights into the architecture and function of matter.